We seek to advance the understanding of the physiology and pathophysiology of the hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes. The roles of the stress-related hormones corticotropin-releasing hormone (CRH) and glucocorticoids in normal and disease states are being examined, and clinical applications for these hormones and their antagonists are sought. We have demonstrated that several human states are characterized by hyperactivity or hypoactivity of the central stress system, which explains not only mood changes but also the propensity of patients with such disorders to develop developmental, metabolic, cardiovascular or autoimmune complications. We are currently performing preclinical studies with the newly discovered nonpeptide, oral, CRH type 1 receptor antagonist, antalarmin, which show that such an antagonist may be useful in a large number of states characterized by hyperactivity of the stress system, such as depression, anorexia nervosa and idiopathic insomnia. [unreadable] At the level of the stress system target tissues, we have elucidated the molecular pathophysiology of sporadic and familial glucocorticoid resistance by defining novel mutations and/or deletions of the glucocorticoid receptor gene leading to abnormally functioning or decreased receptors. In the same area, we have described inflammation-induced glucocorticoid resistance and glucocorticoid secretion insufficiency in the acute respiratory distress syndrome. We have also found that CLOCK/BMAL1, the self-oscillating transcription factors that generate circadian rhythms in both the central nervous system and periphery, rhythmically repressed GR-induced transcriptional activity, indicating that CLOCK/BMAL1 functions as a reverse phase negative regulator of glucocorticoid action in target tissues, possibly by antagonizing the biologic actions of diurnally fluctuating circulating glucocorticoids. Furthermore, the noncoding (nc) RNA Gas5, which accumulates in growth-arrested cells, but whose physiologic roles are not known as yet, and the adenosine 5 monophosphate-activated protein kinase (AMPK), a master regulator of energy homeostasis, sensing energy depletion inside the body and stimulating pathways that increase fuel uptake and save on peripheral supplies, regulated GR-induced transcriptional activity. The former accomplished this by acting as a decoy RNA GRE, the latter by phosphorylating the GR. These results indicate that the biologic actions of the HPA axis are regulated at the level of the target tissues by the nutritional state and availability of energy resources. [unreadable] We have determined that Vpr and Tat, two small HIV-1 accessory proteins, are potent coactivators of the glucocorticoid receptor, causing marked target tissue glucocorticoid hypersensitivity, the presence of which may explain some of the clinical features and pathogenesis of AIDS. Also, we have made advances in understanding the pathophysiology and treatment of congenital adrenal hyperplasia, by demonstrating that these patients have epinephrine deficiency and insulin resistance, which leads to ovarian dysfunction and metabolic abnormalities, while we have shown that treatment with androgen antagonists combined with aromatase inhibitors decreases their need for glucocorticoid therapy resulting in a better height outcome. Finally, we have demonstrated that the carrier state of the 21-hydroxylase deficiency, a common condition, is associated with significant psychiatric and physical morbidity. Recently we have initiated studies examining the participation of the mitochondria in the stress response. We have created a human mitochondrial gene database and microarray chip and have determined the major input of glucocorticoids in the regulation of the enzyme monoaminoxidase and generation of oxygen radicals in muscle cells.